Commentary
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.
Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.
One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.
The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.
Applications for Clinical Practice
CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.